International Journal of Molecular Sciences Review New Viral Facets in Oral Diseases: The EBV Paradox Lilit Tonoyan 1,*, Séverine Vincent-Bugnas 1,2 , Charles-Vivien Olivieri 1 and Alain Doglio 1,3,* 1 Faculté de Chirurgie Dentaire, Université Côte d’Azur, EA 7354 MICORALIS (Microbiologie Orale, Immunothérapie et Santé), 06357 Nice, France; [email protected] (S.V.-B.); [email protected] (C.-V.O.) 2 Pôle Odontologie, Centre Hospitalier Universitaire de Nice, 06001 Nice, France 3 Unité de Thérapie Cellulaire et Génique, Centre Hospitalier Universitaire de Nice, 06103 Nice, France * Correspondence: [email protected] (L.T.); [email protected] (A.D.) Received: 3 October 2019; Accepted: 20 November 2019; Published: 22 November 2019 Abstract: The oral cavity contributes to overall health, psychosocial well-being and quality of human life. Oral inflammatory diseases represent a major global health problem with significant social and economic impact. The development of effective therapies, therefore, requires deeper insights into the etiopathogenesis of oral diseases. Epstein–Barr virus (EBV) infection results in a life-long persistence of the virus in the host and has been associated with numerous oral inflammatory diseases including oral lichen planus (OLP), periodontal disease and Sjogren’s syndrome (SS). There is considerable evidence that the EBV infection is a strong risk factor for the development and progression of these conditions, but is EBV a true pathogen? This long-standing EBV paradox yet needs to be solved. This review discusses novel viral aspects of the etiopathogenesis of non-tumorigenic diseases in the oral cavity, in particular, the contribution of EBV in OLP, periodontitis and SS, the tropism of EBV infection, the major players involved in the etiopathogenic mechanisms and emerging contribution of EBV-pathogenic bacteria bidirectional interaction. It also proposes the involvement of EBV-infected plasma cells in the development and progression of oral inflammatory diseases. A new direction for preventing and treating these conditions may focus on controlling pathogenic EBV with anti-herpetic drugs. Keywords: Epstein–Barr virus; lichen planus oral; periodontal diseases; Sjogren’s syndrome; etiopathogenesis of oral inflammatory diseases; viral-bacterial synergism; plasma cells 1. Introduction With all due respect to microbial flora, the mouth is home to the second most diverse microbial community in the human body, housing a variety of microbes, including bacteria, viruses and fungi [1]. The oral cavity is also the main portal of entry for pathogens into the human host. The mouth is not a homogeneous environment for the resident microbes but constantly changing distinct bio-habitats, such as teeth, gingival sulcus, attached gingiva, tongue, cheek, lip, hard and soft palate, which are occupied by different microbial communities. The oral microbial community is normally in equilibrium and lives in symbiosis with a healthy host. The transition in the microflora towards disease development happens as a result of a complex interaction of microbial-specific traits, host immune responses and ecosystem-based factors [2,3]. The bacteria and fungi have been traditionally the hub in the discussions of microbiological aspects of oral diseases. The bacteria and fungi responsible for the most common oral diseases are now better known, while viruses have a more questionable reputation. Viruses, though, are probably more involved in oral diseases than has been previously recognized [4]. Indeed, the oral mucosal surfaces are also associated with a complex viral population (virobiota). Our current understanding of how these viruses replicate and persist within the oral tissues is still in infancy and better knowledge of the oral virobiota represents an emerging facet of modern oral biology. The Int. J. Mol. Sci. 2019, 20, 5861; doi:10.3390/ijms20235861 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2019, 20, 5861 2 of 17 analysis of viral diversity has been notably afforded by the advances in sequencing and bioinformatics technologies improving our knowledge of oral virobiota. Many of the viruses identified so far in the human virome are bacteriophages, opening a way to new exciting discoveries about the role of bacteriophages in oral microbiology [5]. In addition, major eukaryotic viral families occurring in the oral cavity and contributing to the propagation of oral diseases in adult human individuals include herpesviruses, papillomaviruses, picornaviruses/enteroviruses, retroviruses [6–9] and the recently identified redondoviridae [10]. The present review will be particularly focused on Epstein–Barr virus (EBV), a herpesvirus showing a typical oral ecology and commonly found in most inflammatory oral lesions. This viral infection, usually considered as a benign infection in most healthy individuals, is however associated with various malignancies, functional abnormalities of immunity and oral diseases [11–13]. Whether EBV is only an opportunistic agent which benefits from inflammatory conditions to actively replicate, or a critical pathogen able to trigger and worsen oral diseases remains an intriguing unsolved question. This review aims to bring new light to this paradox. 2. EBV Biology Herpesvirus species are one of the most prevalent viral families in the oral cavity. Herpesviruses have coexisted with the human host over millions of years, developing sophisticated strategies to stay in their host for its lifetime. Following a primary infection, herpesviruses manifest a latent infection in a small number of specific cellular sites, minimizing viral production. This allows them to evade the immune system and persist in the host with minimal impact on them [14]. Acute infection and periodic reactivation, on the other side, allows the infectious virus to spread to new hosts [13,15,16]. EBV belongs to this ancient and highly successful herpesvirus family. It is often said that EBV infection is one of the most successful chronic viral infections in humans. Indeed, EBV is strikingly ubiquitous in humans, establishing a persistent, almost benign infection in over 90% of the world’s adult population for their entire life [13]. Asymptomatic primary infection with EBV typically occurs during infancy and early childhood. In contrast, delayed primary infection is contracted in young adults who have not been exposed to EBV early in life. Symptomatic acute infection at this time in 25–80% of cases manifests as infectious mononucleosis (IM) [15,17], dubbed the “kissing disease”. Most often, EBV is transmitted from the carrier to naïve host orally through direct contact with virus-infected saliva, such as with kissing, also via blood and semen during sexual contact, blood transfusion and organ transplantation [18]. EBV can infect a variety of cell types under different circumstances. It preferentially colonizes B lymphocytes, but can also infect epithelial cells (EC), occasionally, T lymphocytes, natural killers (NK), monocytes, smooth muscle cells and, possibly, also follicular dendritic cells (DC) [19]. There has been a controversy over which cell type is infected first by EBV following salivary transmission, being either oropharyngeal ECs or directly B cells. It has been speculated that EBV actually first infects the oropharyngeal ECs, where it replicates, and then is released to infect B cells co-localized in the lymphoepithelial structures [15] (Figure1). An alternative model suggests, that EBV enters into the crypts of lymphoepithelium of the tonsils via saliva, crosses the epithelial barrier (which is often only one cell thick, immediately above the bed of lymphocytes) and directly infects naïve B cells [20]. In agreement with this last model, Dunmire and co-authors [21] showed that EBV viral genomes are detected at low levels in blood about three weeks before any IM symptoms, suggesting early systemic diffusion of EBV-infected B cells before epithelial amplification in the oral cavity. EBV entry into the target cells is the fundamental part of the viral infectivity and happens as a result of the fusion of viral and host membranes mediated by viral glycoproteins and cellular receptors. Our understanding of EBV entry into the different cell types is incomplete, but some of the major players involved in B cell and EC infections have been identified [19]. EBV envelope glycoprotein gp350/220 has a major role in the attachment of EBV to the complement receptor type 2 or cluster of differentiation 21 (CR2/CD21), a B cell-specific surface receptor. The internalization of EBV requires Int. J. Mol. Sci. 2019, 20, 5861 3 of 17 also the interaction of another viral glycoprotein gp42 with human leukocyte antigen (HLA) class II molecules on B cells. On the other hand, the attachment of EBV to ECs is a more complicated event and is less understood. In ECs lacking CD21 and HLA class II, two possible attachment mechanisms have been proposed: (1) entry via gHgLR alone—two viral glycoproteins gH and gL directly bind to gHgLR receptors on ECs; (2) entry via integrins and gHgLR—EBV transmembrane envelope glycoprotein BMRF2 interacts with integrins on ECs (β1 family and α5β1) possibly initiating signaling events, while gHgL interacts with gHgLR. Previous studies indicated that the integrins αvβ5, αvβ6 and αvβ8 function as gHgLR receptors for EC entry [22,23]. However, more recent studies have identified the ephrin receptor A2 (EphA2) as a critical player for EBV EC entry [24,25]. It was notably shown in these studies that EphA2 specifically